1. Field of the Invention
The present invention relates generally to the fields of cell biology, molecular biology and medicine. More particularly, it concerns use of antisense oligomers to PLA2 (phospholipase A2) to inhibit PLA2 protein expression and enzyme activity, and to treat diseases and disorders associated with induced expression of PLA2, especially cPLA2 (cytosolic PLA2), and sPLA2 (secretory PLA2).
2. Description of Related Art
Sepsis is a prevalent disease which leads to death or disability by multiple organ failure. Although many pharmacological agents and therapeutic interventions have been developed for the treatment of sepsis and septic shock, the problems of organ dysfunction involving liver, heart, lung, kidney and circulating blood cells, etc., continue to affect millions of people throughout the world (Angus et al., 2001; Parrillo, 1991; Centers for Disease Control, 1990; Chaby, 1999). Most of the pharmacological agents that have been developed to control sepsis and septic shock have met with limited success because they are aimed at specific organ or cell type. Since sepsis elicited PLA2 overexpression in many organs and tissues, and the overexpressed PLA2 is closely linked to multiple organ failure (Vadas and Pruzanski, 1983; Liu, 1990; Endo et al., 1995; Nagase et al., 2000), a logical approach for treatment of sepsis is to prevent the overexpression of PLA2 genes.
Antisense inhibition has been developed for the treatment of diseases resulting from overexpression of genes (Jansen and Zangemeister-Wittke, 2002; Phillips, 2001; Jaaskelainen and Urtti, 2002; Riijcken et al., 2002; Griesenbach et al., 2002; Merdan et al., 2002). An antisense oligonucleotide (ODN) is a single-stranded synthetic DNA with a specific sequence to hybridize a specific mRNA. The hybridization leads to a reduction in the protein level. The specificity and uniqueness of the antisense ODN toward single gene and its efficient cellular uptake and wild distribution among many organs (Phillips et al., 2000; Phillips, 2001; Jaaskelainen and Urtti, 2002; Mohuczy and Phillips, 2002), make antisense ODN strategy a most desirable approach for treatment of sepsis, because sepsis-induced PLA2 overexpression takes place in multiple organs. Other advantages include that antisense ODN can be used as a drug and it has an action that lasts for either days for short-term or weeks for long-term treatments. In addition, antisense ODN is safe and it fails to induce toxic effects such as inflammation and immune responses (Phillips et al., 2000; Phillips, 2001; Jaaskelainen and Urtti, 2002; Mohuczy and Phillips, 2002). Additional benefit of employing antisense ODN strategy to correct sepsis-elicited PLA2 overexpression resides on its ability to “knock-down” rather than “knock-out” the overexpressed gene so that it reduces overactive protein yet permits normal physiology (Phillips, 2001).
Many potential therapies that inhibit PLA2 activities, the subsequent enzymatic pathways, and mediators, have been investigated in clinical trials (Abraham et al., 2003; Bernard et al., 1997; Opal et al., 2004) and animal studies (Nagase et al., 2003) Inhibition of sPLA2 activity with a selective enzyme inhibitor in patients with sepsis and organ failure had no overall survival benefit (28-day all-cause mortality), but had a significant treatment effect when drug was given earlier, i.e., within 18 hrs from the onset of the first sepsis-induced organ failure (Abraham et al., 2003) Inhibition of cyclooxygenase pathway with ibuprofen in sepsis patients reduced physiological abnormalities but did not improve the rate of survival at 30 days (Bernard et al., 1997). Treatment of sepsis patients with a recombinant human platelet-activating factor (PAF) acetylhydrolase did not decrease 28-day all-cause mortality (Opal et al., 2004) Inhibition of cPLA2 activity by a potent enzymatic inhibitor attenuated acute lung injury induced by lipopolysaccharide in mice (Nagase et al., 2003). The efficacy of the afore-mentioned agents clinically has been less overwhelming. Thus, improved methods for treating sepsis continue to be highly desired.